THYROID GLAND - GENERAL & BLOOD SUPPPLY *Bilobed, lobulated & Scm lang, extending to tracheal ring 6 *Shield shaped & lies on carotid sheath Limited extension upwards by sternothyroid *Can pass inferiorly into mediastinum Note relationship of branching of arteries to pretracheal fascia Superior thyroid artery from external carotid Upper pole Behind sympathetic chain Lateral lobe Inferior thyroid artery from thyrocervical Lower pole’ trunk (other banches are ascending cervical, Isthmus transverse cervical & {on rings suprascapular) 2,3,4) Thyroidea ima (3% from aorta) Note intimate relationship of branches of the inferior thyroid artery to the recurrent laryngeal nerve Function: Produces thyroxine and thyrocalcitonin External carotid a Superior thyroid a Internal jugular v Superior thyroid v ‘Middle thyroid v Inferior thyroid a Thyrocervical trunk Subclavian a Subclavian v Inferior shyt Left brachiocephalic v Lymph to deep coiicl chain odes Isthmus is firmly attached to rings 2,3,4 of tracheaTHYROID GLAND - AXIAL SECTION AT C7 Relations of thyroid gland Posterior: Prevertebral fascia, carotid sheath, parathryoids, trachea Medial: Recurrent laryngeal nerve, trachea, larynx, oesophagus Anterior: Pretracheal fascia, sternohyoid, sternothyroid, venous arch fascia fascia muscles Posterior: Prevertebral fascia, carotid sheath, parathyroids, trachea Medial: Recurrent laryngeal nerve, trachea, larynx, oesophagus Anterior: Pretracheal fascia, sternohyoid, sternothyroidTHYROID GLAND - SURGICAL ASPECTS Inferior thyroid artery Recurrent laryngeal n PARTIAL SUBTOTAL Oma: THYROIDECTOMY THYROIDECTOMY INDICATIONS FOR SURGERY (partial/nodule excision or subtotal) * Excision of solitary nodule of which approximately 15% are cancerous, 40% part of a multinodular goitre and 40% adenoma. # Hyperthyroidism (80% Graves’ disease and 10% multinodular goitre) for failed medical treatment such as poor drug compliance, Large goitre leading to tracheal, oesophageal, or superior vena cava compression, or a retrosternal extension. RISKS OF SURGERY To parathyroid glands. To recurrent laryngeal nerve (most laryngeal muscles) when ligating inferior thyroid artery and to external branch of superior laryngeal nerve (cricothyroid muscle) when ligating superior thyroid artery. Note that right recurrent laryngeal nerve can enter larynx directly from vagus and not pass around subclavian artery VARIATIONS IN RELATIONSHIPS OF RECURRENT LARYNGEAL NERVE TO INFERIOR THYROID ARTERY Deep to Superficial In amongst artery to artery arteryPARATHYROID GLANDS Superior thyroid Pharynx THYROID GLAND aery VIEWED FROM BEHIND Superior gland Oesophagus artery NORMAL POSITIONS ‘AND VARIATIONS. ‘© 4 (3-6) pinkish/brown glands * Weighing 50mg & 6x3x2mm each * Usually lie within pretracheal fascia ‘* Superior (develops from endoderm of dorsal diverticulum of 4th arch). tom Less variation in position '® Inferior (Is dragged down with thymus from 3rd pouch). More variation, even & : into upper mediastinum Recurrent laryngeal ® Blood supply: Inferior thyroid arteries nerve crossing behind Nerves: Sympathetics on arteries for &in amongst the vasoconstriction branches of the inferior =e Histology: * Homogeneous thyroid artery © Very vascular * Small round cells * No follicles © Irregular columns * Function: # Produces parathormone (PTH) * Increases tubular reabsorption of calcium * Decreases tubular reabsorption of phosphate/bicarbonate © Mobilises calcium from bones to give hypercalcaemia and hypercalciuriaeet ASH AAO } Rf i — TOTAL V—_—_—_—_— 2x Lose SESS Ms7uMvsTHRYOID DEVELOPMENT THYROGLOSSAL CYST AND FISTULA FORAMEN CAECUM —— Site of origin of thyroglossal duct between floor of branchial arches 1 and 2 THYROGLOSSAL DUCT Endodermal downgrowth of thyroid epithelium from it. Developing tissue invades hypobranchial mesenchyme which gives capsule and septa © Sites of thyroglossal cysts (move up with protrusion of tongue), remnant thyroid tissue (lingual thyroid), fistulae, sinuses & pyramidal lobe The thyroid grows down from the tongue as a bilobed diverticulum connected back to the tongue by the thyroglossal duct. This duct solidifies. and then usually disappears but can leave thyroglossal cysts, fistulae or “rests” (ectopic bits of thyroid) on the way (blue). These are always in the midline. They move on swallowing or protruding the tongue. Radioactive scans show thyroid tissue even if it is ectopically placed. Note: The ultimobranchial bodies (5th pouch) give "C" cells 1 If developing process goes too farLymph node levels of the neck Level I, submental (IA) and submandibular (IB); level II, upper internal jugular nodes; level III, middle jugular nodes; level IV, low jugular nodes; level V, posterior triangle nodes; level VI, central compartment; level VII, superior mediastinal nodes.Lymph nodes of the head and neck Posterior auricular Preauricular Occipital Parotid Superficial cervical Lower ear and parotid Tonsillar (ugulodigastric) Deep cervical 5 Other nodes of head and neck, ‘occipital scalp, ear, back of neck, ee tongue, trachea, nasopharynx, papal nasal cavities, palate, esophagus maith, apex of tone ‘Submandibular Posterior cervical Cheek, side of nose, lower lip, gums, anterior tongue This drawing schematically depicts the major lymph nodes in the head and neck area that are likely to be enlarged on physical examination in patients with various local or systemic diseases. The major nodal groups are shown here in bold, with the areas draining into these nodal groups noted when appropriate. While enlargement of both the left and right supraclavicular lymph nodes may reflect disease in the thorax, left supraclavicular nodal enlargement, because of its drainage pattern, may also reflect the presence of abdominal involvement (ie, Virchow node).Regulation of thyroid hormone production Hypothalamus: Circulatory system Conjugated T4 and T3 te $ Stimulatory pathway SS TRH increases the secretion of TSH, which stimulates the synthesis and secretion of T3 and 74 by the thyroid gland. T3 and T4 inhibit the secretion of TSH, both directly and indirectly by suppressing the release of TRH. T4 is converted to T3 in the liver and many other tissues by the action of T4 monodeiodinases. Some T4 and T3 is conjugated with glucuronide and sulfate in the liver, excreted in the bile, and partially hydrolyzed in the intestine. Some T4 and T3 formed in the intestine may be reabsorbed. Drug interactions may occur at any of these sites. Inhibitory pathwayThyroid hormone biosynthesis Thyroid hormone synthesis includes the following steps, marked by numbers in the diagram above: 1. I trapping by the Na*/I- symporter into the thyroid follicular cells, 2. Diffusion of I” to the apex of the cells. 3. 4. Transport of I~ into the colloid, via pendrin. Oxidation of inorganic iodide to iodine (1°) by TPO and its incorporation into tyrosine residues within thyroglobulin in the colloid. DUOX2 and DUOXA2 are required for generation of hydrogen peroxide, a substrate for TPO. . Combination of 2 DIT molecules by TPO to form 74, or of MIT with DIT to form T3. . Uptake of thyroglobulin from the colloid into the follicular cell by endocytosis; fusion of the thyroglobulin with a lysosome; and proteolysis and release of T4, T3, OIT, and MIT. Release of T4 and T3 into the circulation. . Deiodination of DIT and MIT by iodotyrosine deiodinase (encoded by YD, also known as iodotyrosine dehalogenase 1 [DEHAL1]), allowing recycling of I~. T3 is also formed from monodeiodination of T4 in the thyroid and in peripheral tissues. T°: iodide; TPO: thyroid peroxidase; DUOX2: dual oxidase 2; DUOXA2: dual oxidase maturation factor 2; DIT: diiodotyrosine; T4: thyroxine (tetraiodothyronine); MIT: monoiodotyrosine; T3: triiodothyronine.FIG. 37.14 Workup of a thyroid nodule. AUS, Atypia of undetermined significance; FLUS, follicular lesion of Undetermined significance; FN, follicular neoplasm; FNA, fine-needle aspiration biopsy; SFN, suspicious for fol- licular neoplasm: TSH, thyroid-stimulating hormone.ACR T-RADS ‘Spongtorm Composed “Anecoe: Appts ocysic or | Tatersnaratdr Sroud be “Lotuiate Pronsion into Large comet aritacts. ‘recoriarty (50%) ot smat_ | almost compete, cysic nodes. | assessed ona aneverse mage | adjacent tesue. shaped 1 mm neste ‘Gye spaces Do not aod ‘win measurements paral 1 components. ‘inner ports tor other yperecracteoecno! ‘Sound beam for het and egutar. aggee, spisate, ot ‘categories ‘mypoecto'c Compared 10 Serpenciouarto souna Beam tr | sharp anges Macrocaltcatons: Cause ‘scent parenchyma. wan. scovatic shadowing. Mazed cyste ard sok Assign Extathyrodal extension: Otvious ports or pedomnant sold” | Very hypoechotc More ‘This can usualy be assessed by | invasion = magrancy. Peripheral Complete oF ‘component. Inypoechoe tan sap muscies. | visual nspecton incomplete along margin. ‘Assign 0 poies # margin cannot ‘pasar 2 ponts Wcamponton | Assign 1 pnt echagenty be cenomined. ‘Punctate echogenic fot May ‘cannot be otermaea because | cannot be acters nave smal comet al arlact ‘eachcasen. "Role o ascusson of papa merocarenomas for 5-9 TAS nodes, FIG. 37.16 The American College of Radiology (ACA) Thyroid imaging, Reporting and Data System (TLRADS) lexicon, TR levels, and criteria for fine-needle aspiration biopsy. (From Tessier FN, Middleton WD, Grant EG, ‘etal. ACR Thyroid Imaging, Reporting and Data System (TI-RADS): white paper of the ACR THRADS Committee. J Amn Coll Radiol. 2017;14'587-595 )ATA NODULE SONOGRAPHIC PATTERN RISK OF MALIGNANCY High Suspicion 70%-90% “<= : ered Peer eee ey Kia ba ae (7 dae honest) Intermediate Suspicion 10%-20% Low Suspicion 5%-10% Very low Suspicion <3% a ties cay yao A parvaty cystic no alllus tester Benign <1% FIG. 37.15 American Thyroid Association (ATA) nodule sonographic patterns and risk of malignancy. (From Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for pa tients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26:1-133.)Evaluation and management of patients with medullary thyroid cancer diagnosed on the basis of fine needle aspiration biopsy of a thyroid nodule Thyroid nodule: FINA diagnosis of MTC RET RET + or RET unknown Evaluate for HPTH Evaluate for PHEO nooo eS Hosent| [Present xattime] [Absent] [Present unilateral ore or bateral ADK rir to TIX Preoperative Gm <300 palm Preoperative tn 7500 palm ¥ ¥ “Tx with or thou cervical ND Imaging procedures fo echode depending an US, serum Cin levels Presence of metastatic HTC and intraoperative findings MO, proceed to TIX with or Mi Te thou carvial UND, depending on neck US results a tnd serum Gon bevels Patients with progresive] [Treat regional | Systemic disease ‘euate Consider EBRT tothe neck onaiderEBRT =the neck] [Systemic therapy] [Clinical bil WF etensive nodal disease fFentansve rode! dsesse, = ner Tesidal MTC, or extension residue HTC, or extension FMT beyond the SFUTE beyond the thyroid ADX: adrenalectomy; Ctn: calcitonin; CEA: carcinoembryonic antigen; EBRT: external beam radiotherapy; FNA: fine needle aspiration; HPTH: hyperparathyroidism; LND: lymph node dissection; MTC: medullary thyroid cancer; M: metastatic MTC; PHEO: pheochromocytoma; TKI: tyrosine kinase inhibitor; TTX: total thyroidectomy; US: ultrasound. * Ctn and CEA are measured to determine whether they are produced by the tumor, and if so, as a baseline for comparison with the results obtained after surgery. In addition, patients with preoperative Ctn >500 pg/mL require additional preoperative imaging.Management of patients following thyroidectomy for medullary thyroid cancer Status 11x v * Physical exam and US of the neck = Measure serum levels of Ctn, CEA, ‘TFT s, and TSH every 6 to 12 months a Cin undetectable or Detectable Cin but <150 pg/mL and ‘Gin >150 pa/mt within normal range ro evidence of persistent or recurrent | MTC on physical exam or US v 1f physical exam and * Physical exam and US of * Imaging procedures* US remains normal, neck every six months to detect metastases ‘evaluate every six months ‘= Measure serum Ctn and CEA for one year, then annually ‘every three to six months a v to determine doubling times #= If serum Cin >150 pg/ml. Imaging Imaging perform imaging procedures*| | positive negative to detect recurrent MTC J | * Consider treating regional disease * Physical exam and by surgical resection, EBRT, or repeat imaging studies ‘other modalities depending on site every 6 to 12 months and associated risks ‘= Measure serum Ctn and CEA * Patients with progressive systemic ‘every three to six months disease should be treated with to determine doubling times systemic therapy (preferentially a TKI), oF participate in a clinical trial CEA: carcinoembryonic antigen; CT: computed tomography; Ctn: calcitonin; EBRT: external beam radiotherapy; MRI: magnetic resonance imaging; MTC: medullary thyroid cancer; TFT: thyroid function test; TKI: tyrosine kinase inhibitor; TSH: thyroid-stimulating hormone; TTX: total thyroidectomy; US: ultrasound. * Additional imaging includes CT or MRI of neck, chest, and abdomen; bone scan or bone MRI in patients suspected of having skeletal metastases.Causes of thyroid nodules Benign Multinodular (sporadic) goiter ("colloid adenoma") Hashimoto's (chronic lymphocytic) thyroiditis Cysts (colloid, simple, or hemorrhagic) Follicular adenomas Macrofollicular adenomas Microfollicular or cellular adenomas NIFTP (noninvasive follicular tumor with papillary- like nuclear features)* Hurthle cell (oxyphil cell) adenomas Macro- or microfollicular patterns Malignant Papillary carcinoma Follicular carcinoma Minimally or widely invasive Oxyphilic (Hiirthle cell) type Noninvasive follicular thyroid neoplasm with papillary-like nuclear features Medullary carcinoma Anaplastic carcinoma Primary thyroid lymphoma Metastatic carcinoma (breast, renal cell, others) * Previously called noninvasive follicular variant papillary cancer. The nodule requires surgical excision for diagnosis.ATA (2015): FNA guidance for thyroid nodules Sonographic Ultrasound Estimated risk of pattern features malignancy High suspicion Solid hypoechoic nodule >70 to 90%* or solid hypoechoic component of a partially cystic nodule WITH one or more of the following features: Irregular margins (infiltrative, microlobulated), microcalcifications, taller than wide shape, rim calcifications with small extrusive soft tissue component, evidence of extrathyroidal extension Intermediate Hypoechoic solid nodule 10 to 20% suspicion with smooth margins WITHOUT microcalcifications, extrathyroidal extension, or taller than wide shape Low suspicion Isoechoic or 5 to 10% hyperechoic solid nodule, or partially cystic nodule with eccentric solid areas, WITHOUT microcalcification, irregular margin or extrathyroidal extension, or taller than wide shape Very low suspicion Spongiform or partially <3% cystic nodules WITHOUT any of the sonographic features described in low, intermediate, or high suspicion patterns Benign Purely cystic nodules <1% {no solid component) Consider biopsy (FINA size cutoff, largest dimension) Recommend FNA at 21 cm Recommend FNA at 21 cm Recommend FNA at 21.5 cm Consider FNA at 22 cm Observation without FNAis also a reasonable option No biopsy® NOTE: Ultrasound-guided FNA is recommended for cervical lymph nodes that are sonographicallyBethesda system diagnostic categories for reporting thyroid cytopathology II III IV VI Bethesda class Diagnostic category Nondiagnostic (unsatisfactory) Benign Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS) Follicular neoplasm (or suspicious for follicular neoplasm) Suspicious for malignancy Malignant Cancer risk 5 to 10% 0 to 3% 6 to 18% 10 to 40% 50 to 75% 97 to 99%Ultrasound features associated with thyroid cancer risk in adults Ultrasonographic features that are associated with an increased risk of thyroid cancer Hypoechogenicity Solid composition Punctate echogenic foci (microcalcifications) Infiltrative/irregular margins Taller-than-wide shape Associated suspicious lymphadenopathy Ultrasonographic features that are associated with a lower risk of thyroid cancer Isoechoic or hyperechoic Spongiform appearance Simple cysts Comet-tail artifact within a cystic nodule Uninterrupted eggshell calcificationClassification of multiple endocrine neoplasia type 2 Type 2A MENZ2A classical (medullary thyroid cancer, pheochromocytoma, primary hyperparathyroidism) MENZ2A with cutaneous lichen amyloidosis MENZ2A with Hirschsprung disease Familial medullary cancer without pheochromocytoma or parathyroid hyperplasia Type 2B Medullary thyroid cancer Pheochromocytoma Other Mucosal neuromas Intestinal ganglioneuromas Marfanoid habitusBlack thyroid syndrome (A) Gross thyroid specimen with diffuse black discoloration from tetracycline use. (B) LM image showing black pigment deposition in the thyroid colloid. (©) Higher magnification of LM demonstrating black material within the colloid and the surrounding follicular cells. (D) Electron microscopy image showing black pigment within cellular lysosomes. LM: light microscopy.Causes of hyperthyroidism Hyperthyroidism with a normal or high radioiodine uptake Autoimmune thyroid disease Graves’ disease Hashitoxicosis Autonomous thyroid tissue (uptake may be low if recent iodine load led to iodine-induced hyperthyroidism) Toxic adenoma Toxic multinodular goiter TSH-mediated hyperthyroidism TSH-producing pituitary adenoma Non-neoplastic TSH-mediated hyperthyroidism Human chorionic gonadotropin-mediated hyperthyroidism Hyperemesis gravidarum Trophoblastic disease Hyperthyroidism with a near absent radioiodine uptake Thyroiditis Subacute granulomatous (de Quervain's) thyroiditis Painless thyroiditis (silent thyroiditis, lymphocytic thyroiditis) Postpartum thyroiditis Amiodarone (also may cause iodine-induced hyperthyroidism) Checkpoint inhibitor-induced thyroiditis Radiation thyroiditis Palpation thyroiditis Exogenous thyroid hormone intake Excessive replacement therapy Intentional suppressive therapy Factitious hyperthyroidism Ectopic hyperthyroidism Struma ovarii Metastatic follicular thyroid cancer Major causes of hyperthyroidism according to the presence of a high or low radioiodine uptake. High uptake indicates increased new hormone synthesis by the thyroid, whereas low uptake indicates release of preformed hormone, exogenous ingestion, or extrathyroidal hormone synthesis.Causes of thyroiditis according to the presence or absence of pain and tenderness Disorder Thyroid pain and tenderness Subacute thyroiditis Infectious thyroiditis Radiation-induced thyroiditis Palpation- or trauma-induced thyroiditis No thyroid pain and tenderness Painless thyroiditis - Occurring postpartum - Associated with drugs Chronic lymphocytic thyroiditis - Postpartum exacerbation Amiodarone-associated thyroiditis Fibrous thyroiditis Synonyms or causes Subacute granulomatous thyroiditis Subacute nonsuppurative thyroiditis de Quervain's thyroiditis Acute or chronic thyroiditis Silent thyroiditis Lymphocytic thyroiditis with spontaneously resolving hyperthyroidism Subacute lymphocytic thyroiditis Postpartum thyroiditis Interferon-alpha Interleukin-2 Lithium Tyrosine kinase inhibitors Checkpoint inhibitor immunotherapy Hashimoto's thyroiditis Postpartum thyroiditis Riedel's thyroiditis Invasive thyroiditisCharacteristic course of thyroiditis (painless, postpartum, or subacute) Hyperthyroid Euthyroid Hypothyroid Recovery - Euthyroidism phase phase phase : Ta and 13, ~ © 24 hour RAT uptake ~———- 1H The initial thyroid inflammation damages thyroid follicles and activates proteolysis of the thyroglobulin stored within the follicles. The result is unregulated release of large amounts of T4 and T3 into the circulation and, therefore, hyperthyroidism. This state lasts only until the stores of thyroglobulin are exhausted because new hormone synthesis ceases. As the inflammation subsides, the thyroid follicles regenerate and thyroid hormone synthesis and secretion resume. There may be a transient period of hypothyroidism and increased TSH secretion before thyroid secretion becomes normal again. However, some patients have only a hyperthyroid or hypothyroid phase. T4: thyroxine; T3: triiodothyronine; RAI: radioiodine; TSH: thyroid- stimulating hormone.ATA risk stratification system to estimate risk of persistent/recurrent disease Low risk Papillary thyroid cancer with all of the following present: = No local or distant metastases = All macroscopic tumor has been resected * No invasion of locoregional tissues = Tumor does not have aggressive histology (aggressive histologies include tall cell, insular, columnar cell carcinoma, Hiirthle cell carcinoma, follicular thyroid cancer, hobnail variant) = No vascular invasion = No 131, uptake outside the thyroid bed on the post- treatment scan, if done = Clinical NO or <5 pathologic N1 micrometastases (<0.2 cm in largest dimension)* Intrathyroidal, encapsulated follicular variant of papillary thyroid cancer* Intrathyroidal, well- differentiated follicular thyroid cancer with capsular invasion and no or minimal (<4 foci) vascular invasion* Intrathyroidal, papillary microcarcinoma, unifocal or multifocal, including BRAF V600E mutated (if known)* Intermediate risk Any of the following present: Microscopic invasion into the perithyroidal soft tissues Cervical lymph node metastases or 131] avid metastatic foci in the neck on the post-treatment scan done after thyroid remnant ablation Tumor with aggressive histology or vascular invasion (aggressive histologies include tall cell, insular, columnar cell carcinoma, Hurthle cell carcinoma, follicular thyroid cancer, hobnail variant) Clinical N1 or >5 pathologic N1 with all involved lymph nodes <3 cm in largest dimension* Multifocal papillary thyroid microcarcinoma with extrathyroidal extension and BRAFV600E mutated (if known)* High risk Any of the following present: Macroscopic tumor invasion Incomplete tumor resection with gross residual disease Distant metastases Postoperative serum thyroglobulin suggestive of distant. metastases Pathologic N1 with any metastatic lymph node 23.cmin largest dimension* Follicular thyroid cancer with extensive vascular invasion (>4 foci of vascular invasion)*Approach to the management of patients with newly diagnosed anaplastic thyroid cancer expedited aging Obtain sample uring ether core bopey of fine naadle apiration for: ‘Rapid testing for BRAF VEDOE mutation {nett generaton melecular sequencing (# avalable) to Mently other argetabie mutsione Ws elas ios i ‘th edition ADEE staging VAY Confined tothe thyroid (rr3an0, Mo) (138, Terni, mo) {RAF VeGOE mutton atiied ‘BRAF WED0E matin aba or now (iis any ts amr) ¥ ¥ What ithe AICCLT wage? Whats the AICCTT stage? ¥. + ¥ ¥ ¥ Biage NB or Hage NE ‘Stage WA Stage 8 ‘Sage ve i * 4 + [Options include ‘pions ica abrafenibohus vamatinb| | surgery, chemoradiation, | | surgery, chemoradiation, | | * Targeted therapy ‘Targeted therapy ‘ehowed by ersuaton of | | flowed by chsoreaton an | | load by sosarvation and | | = Chororadhaton flowed by + Chemoradiation Tesense to Berany ‘tew-ap mowing Talew-up maging ‘Sbrervation and fobow-up maging | | = Cina! tile + Best supportive care a) esectable Not resectabe Bape NS ‘Biage NE ¥v v Sargey, chemoradiation, Some, folowed by observation and || restart darafen pas Tol uo maaieg ‘wametin This algorithm is intended for use in newly diagnosed, untreated patients with anaplastic thyroid cancer who do not require emergency intervention to secure the aitway or avert impending neurovascular compromise. For use in conjunction with UpToDate content on anaplastic thyroid cancer, AJC: American Joint Committee on Cancer; PET: positron emission tomography; CT: computed tomography; MRI: magnetic resonance imaging, * Neck ultrasound, PET/CT (neck to pelvis), brain MRI or CT. All anaplastic cancers are considered stage IV cancers. Best supportive care/hospice is an alternative to mutational testing if aggressive care is not desired. ‘§ Specific inhibitors of oncogenic ALK, NTRK, or RET fusion mutations can be considered for unresectable stage IVB disease or stage IVC disease, preferably within the context of a clinical trial. A Surgery followed by chemoradiation Is an alternative in patients with resectable IVB disease, © Consider surgery for resectable cervical disease if low volume M1, followed by chemoradiation. 5 If unfavorable response to dabrafenib plus trametinib, options include chemoradiation, clinical trials, and best supportive care,